US Device Mfg Sues UK Cardiologist for Truth Telling

“A senior heart specialist is being sued for libel. Not for making damaging allegations about a colleague, but because he questioned the benefits of a surgical device used to close holes in the heart (called PFOs). Around 25,000 people have had the device inserted.

The sorts of question Dr Peter Wilmshurst has been asking are the ones you’d want answers to: Does it work well? Is it being used on the right patients?

Yet the American company, NMT Medical, which makes the device claims that by talking about his concerns, Dr Wilmshurst has breached a confidentiality agreement. The company has demanded that he apologises and pays damages.”

Dr Wilmshurst had been a consultant and joint principal investigator on a multi-site clinical trial (MIST) that tested the NMT device, Starflex, to determine whether people who suffered from migraine headaches would be relieved of migraines by undergoing PFO closure with the device. The MIST study failed to confirm the migraine hypothesis. The dispute revolves around the effectiveness of the NMT device to close PFOs, which increase the risk for stroke. And an editorial in the journal, Circulation , by Dr. John Carroll (Univ. of Colorado) raised concerns about multiple discrepancies within the study.

According to Dr. Wilmshurst, each patient in the MIST study, had echocardiograms: one before the operation, another, six months later. The surgeons who did the operations reported that 94% of the surgeries had been successful. But Dr Wilmshurst states that he reviewed all the echocardiograms from all the MIST study sites and he found that around 30% had signs indicating that some blood was going the wrong way. His finding was confirmed by another researcher.

MIST of Confusion:
The MIST trial results that were presented at a major cardiology conference in the U.S. in 2007 and published online in 2008 in the journal, Circulation, made no mention of the echocardiogram review and findings.
Instead, the company said that Starflex had successfully closed 94% of PFOs.
Dr. Wilmshurst made a separate presentation outlining his concerns.

Dr. Wilmshurst refused to sign off on the published article, in part, he says, because it didn’t mention the echocardiographic review and because he was never given access to the patient-level data from the study. Neither he nor his colleague at Shrewsbury Hospital, Dr Simon Nightingale, are listed as co-authors.

Another cardiologist, Dr Jonathan Tobis (UCLA), also raised questions about the study when follow-up data were presented at the TCT (2007) meeting. In 2008 he stated:

“the MIST trial provides an excellent case example where interests of researchers, business entities, and government supervising agencies are openly in conflict and reveal the forces that shape the current scientific environment of industry-sponsored clinical research.” http://www.theheart.org/article/864751.do

Indeed, the case is reminiscent of the dispute between Dr. Aubrey Blumsohn, a metabolic bone disease specialist at the University of Sheffield, and Proctor and Gamble-the underlying issue in both cases is scientific integrity and collision with commercial interests. [link]

A noteworthy welcome added facet to the NMT-Wilmshurst dispute:
The active involvement of Professor Sir John Lilleyman, head of the National Research Ethics Service which oversaw the MIST trial, who expressed concern about the conflicting results of echocardiogram reviews, and he worries that some patients in the trial may believe their PFO was closed when it wasn’t:

“The company assured me the results would be published and the issues dealt with. I’ve seen no sign of that.I believe we may have a duty of care to those patients.”

Prof. Lilleyman told heartwire:

“Ignoring the spat between Peter Wilmshurst and NMT, basically what I’m concerned about is that we don’t know what the status of these patients is, and the only way to find out is to review their original scans with an independent, disinterested expert and possibly scan some of them again if the data are nonexistent or noninterpretable.”

We thank Dr Wilmshurst for bringing this case to our attention. Dr. Wilmshurst says he won’t be intimidated by the libel action, and says: ‘I’m prepared to stick my head above the parapet because I think these things are important.” Indeed, he has a history of standing up for what he believes in. If only more doctors followed suit, the integrity of the medical profession
might be restored.

A senior heart specialist is being sued for libel. Not for making damaging allegations about a colleague, but because he questioned the benefits of a surgical device used to close holes in the heart.

Around 25,000 people have had the device inserted, and the sorts of question Dr Peter Wilmshurst has been asking are the ones you’d want answers to: Does it work well? Is it being used on the right patients?

Yet the American company, NMT Medical, which makes the device claims that by talking about his concerns, Dr Wilmshurst has breached a confidentiality agreement. The company has demanded that he apologises and pays damages.

Dr Wilmshurst is not claiming that the heart device is dangerous, just that it is ineffective.
Dr Wilmshurst’s relationship with NMT Medical began cordially. The consultant cardiologist at the Royal Shrewsbury Hospital was commissioned to be joint principal investigator on a big trial, known as MIST, designed to test the theory that closing a hole in patients’ hearts with a device called Starflex could reduce migraines.

Surprisingly, 20 per cent of adults have a such a hole, known as a PFO. This is different from the life-threatening hole that occasionally has to be closed in the heart of newborn babies. If you have a PFO, it means some of your blood goes the wrong way – directly to the brain rather than through the lungs, putting you at risk of conditions such as stroke.

The one thing everyone agrees on is that the device didn’t help people with
migraine: of the 70 patients who had the operation, only three had any improvement in their migraine.

The controversy is over whether the device actually closed the PFOs. That’s because even if it didn’t work as a migraine treatment, it might still be ‘sold’ as a way of closing PFOs.

As part of the trial, each patient had echocardiograms – ultrasound videos of the heart at work, known to specialists simply as ‘echoes’. One before the operation, the other, six months later. ‘It had been agreed that all the records of the echoes would come to me to assess whether the PFOs had been successfully closed,’ says Dr Wilmshurst. Although the surgeons doing the operations reported that 94 per cent had been successful, that wasn’t what Dr Wilmshurst saw. ‘Around 30 per cent had signs that some blood was going the wrong way,’ he says. When Dr Wilmshurst reported this, plans for him to review echoes in a follow-up trial were dropped and another researcher was called in. The new review found the Starflex had successfully closed more than 90 per cent of the PFOs – but also found that 30 per cent of patients still had blood going the wrong way via a different route.

There was no mention of these findings during the presentation of the results of the trial at a major cardiology conference in the U.S. in October 2007. Instead, the company said that although the procedure had done nothing to help with migraine, Starflex had successfully closed 94 per cent of PFOs.
The evidence that the device might not be as effective as had been claimed was simply ignored.

Wilmshurst talked to a journalist about what appeared to be a missing discussion of the evidence from echoes, and added that he had not been able to see the trial’s full data. The manufacturer denied there had been any reviews of echocardiograms. What’s more, it said, Dr Wilmshurst had breached a confidentiality agreement by raising these issues and had been dropped from the trial as a result. The dispute was reported on an academic website specialising in cardiology – heart.org. It was this that triggered the libel suit.

NMT vice-president Richard Davis suggests Dr Wilmshurst’s objections were sour grapes. ‘It is his long-held belief that closing the PFO would help with migraine,’ he says. ‘This is why he is trying to make out the device is not effective – to protect his theory.’

Dr Wilmhurst was not the only expert concerned about the trial. Professor Sir John Lilleyman, head of the National Research Ethics Service which oversaw the MIST trial, is concerned about the conflicting results of echocardiogram reviews. ‘The company assured me the results would be published and the issues dealt with,’ he says. ‘I’ve seen no sign of that.’

Professor Lilleyman is also worried some patients in the trial may believe their PFO was closed when it wasn’t: ‘I believe we may have a duty of care to those patients.’
Dr Wilmhurst won’t be intimidated by the libel action and has a history of standing up for what he believes in. More than 25 years ago, he was threatened with the courts if he didn’t keep quiet about unfavourable findings about a drug used for heart failure. He also fended off legal threats that followed an article he wrote for the BMJ some years later, which revealed how senior doctors had concealed serious professional misconduct and research fraud for a decade.

Dr Richard Smith, a former editor of the British Medical Journal, describes Dr Wilmshurst as ‘perhaps British medicine’s champion whistleblower’.

NMT Medical says Dr Wilmshurst’s allegations have all been raised privately in a multitude of discussions. ‘We’d prefer not to resort to litigation,’
says vice-president Richard Davis. ‘But we cannot allow the company to be libelled.’

Dr Wilmshurst doesn’t intend to back down. He says: ‘I’m prepared to stick my head above the parapet because I think these things are important.’

If you have had an operation to close a PFO and you are worried about whether it has worked, talk to your GP or the cardiologist who performed the operation. ‘If they think it’s necessary, they will run another echocardiogram to check all is well,’ says Dr Vaikom Mahadevan, consultant cardiologist at Manchester Royal Infirmary.
~~~~~~~~~~

http://www.theheart.org/article/944781.do
Journal editors and UK research ethics group raise new questions about MIST migraine/PFO trial Shelley Wood Feb 27, 2009 Dallas TX and London, UK – The journal that published the Migraine Intervention with STARflex Technology (MIST) trial results, as well as a national research ethics committee in the UK, are raising new questions about the study and, specifically, about results of an echocardiographic review the trial sponsor has previously said never even took place.

Editors for Circulation are asking authors of the MIST trial to prepare a correction that will run in the journal, heartwire has learned. Separately, an advisor to the National Research Ethics Service (NRES) in the UK has recommended that the local ethics committee investigate the much-disputed echocardiographic follow-up of patients who underwent patent foramen ovale (PFO) closure in MIST, saying “there’s a problem here that we need to take care of.”

The MIST trial, sponsored by NMT Medical, evolved out of observations that people with PFOs seem to have a higher incidence of migraine than people without and that people who undergo PFO closure for cryptogenic stroke often have fewer migraines following their closure procedures. Disappointingly, the trial found no differences in the number of migraine attacks, total headache days, migraine severity, or migraine frequency among migraineurs randomized to PFO closure or a sham procedure.

As previously reported by heartwire, one of the co-PIs for the MIST study, Dr Peter Wilmshurst (Royal Shrewsbury Hospital, UK), has alleged that NMT asked individual cardiology sites in MIST to send their echo results to him to review-something that hadn’t been part of the original trial protocol. In emails sent to MIST investigators, NMT explains that the review is necessary because of “inconsistencies” in the echoes obtained at the individual centers. Wilmshurst’s review found that roughly one-third of patients appeared to have residual shunting following PFO closure, possibly suggesting that the devices had not successfully closed the PFO in all cases. After Wilmshurst told NMT of his findings, he was dropped as an investigator for the follow-up (MIST 3) study, for what NMT has termed unspecified “protocol violations.”

In Circulation, however, the results published online March 3, 2008 state that just four out of 74 patients had residual shunts (<6%)-a figure also reported by co-PI Dr Andrew Dowson (Kings College Hospital, London, UK) at the TCT 2007 meeting-and make no mention of an after-the-fact review of the echocardiograms [1]. As previously reported by heartwire, Wilmshurst is not listed as an author on the paper; he refused to sign off on a draft prior to publication, in part, he says, because it didn’t mention the echocardiographic review and because he was never given access to the patient-level data from the study. Wilmshurst subsequently wrote to Circulation with his concerns about the published paper and was recently informed by editor-in-chief Dr Joseph Loscalzo that his comments were directly relevant to the manuscript content and that Dowson has been contacted to clarify certain points and to prepare a correction.

Contacted by heartwire, Dowson said he has already prepared the correction for Circulation and that it includes only one minor correction that “didn’t change the meaning of the paper in any way.” Asked whether he would also be addressing the issue of the disputed echo review, Dowson said he would have to check with the journal as to whether he could speak “about those kinds of matters.” “Obviously they have to approve what’s going to be in the correction . . . it hasn’t been finally agreed upon. Circulation will have to accept, or not, the correction we make. We are addressing issues, yes, but there’s not an awful lot I can tell you at the moment.”

Also contacted by heartwire, a Circulation spokesperson would not comment on when the correction would be published or what the specific concerns were.
NMT also declined to comment.
Echo reviews in dispute
In interviews with heartwire in 2007, both NMT Medical and Dowson denied that Wilmshurst’s echo review ever took place, noting that the trial protocol had not included plans for a “core-lab” review but rather stipulated that the individual implanting physicians would check that the device had effectively closed the PFO at six-month follow-up (when patients were unblinded). In contrast to NMT and Dowson, however, Dr Michael J Mullen (Royal Brompton, London, UK), another coauthor on the paper, acknowledged the existence of Wilmshurst’s echo review but was adamant that these data had no place in the paper.

“That review [by Wilmshurst] was totally unsafe, and it would have been completely wrong to have included that in any manuscript, in any form, at any time,” Mullen said in a March 2008 interview with heartwire. “That’s not just my opinion, that was the opinion of a number of individuals involved in the study, who felt that this was a review that was performed after the fact, by an individual whose career has been based on proving the concept that we set out to prove in the study.”

Emails between NMT and other trial investigators, however, clearly show that it was NMT that asked trial investigators to send their six-month follow-up tapes to Wilmshurst for review, suggesting that core-labbing the echoes would “strengthen the study even further.”

Ethics committee concerned about discrepancies Meanwhile, in the UK, Prof Sir John Lilleyman, an advisor to NRES, told heartwire that he has met separately with Wilmshurst, Dowson, the contract research organization that managed the trial (Matrix), and the trial sponsor. Those meetings convinced Lilleyman that there are outstanding ethical questions that need to be addressed with MIST. According to Lilleyman, the NRES has written to the local research ethics authority-the West Midlands Research Ethics Committee-recommending an independent review of the six-month echocardiograms from MIST. NRES has also worked with the West Midlands authority to draft a letter outlining its concerns to Matrix.

“There’s a mess here that needs cleaning up. That’s my take,” Lilleyman told heartwire. “There is uncertainty of the status of the patients who went into this trial and had the device fitted, either as part of the trial or subsequently as part of the control arm who opted to have the device fitted after the trial ended.”

Lilleyman stated that it was his “understanding” that 95% of patients in the control arm also opted to undergo PFO closure after the MIST trial had ended, “based on the encouragement, presumably, of their attending physicians and the early results from the study, which haven’t been borne out by further follow-up,” Lilleyman noted. Wilmshurst estimates that that number may be lower, at about 75%, but he has not had access to the follow-up data.
Lilleyman added that in a conversation with another MIST investigator, he’d been told that the “core-lab” echocardiographic review would be the subject of a further paper, something that hasn’t come to pass, he notes.
“Whether it ever will, I have serious doubts now,” he told heartwire. “So my take on this is that the company, for whatever reason, is reluctant to explore further this question of persistent shunting in patients in this trial. I guess they’re anxious that no data come to life that throws doubt on the efficacy of their device.”

Dowson, in a recent interview with heartwire, acknowledged that he had met with NRES in the past and that at the time “they were happy with the situation.” More recently, he says, he has not heard anything to suggest that the national or local research ethics oversight organizations have any problems with MIST. “I’ve not had any correspondence from them; there’s absolutely nothing that’s been sent. I can only tell you that.”

Legal proceedings ongoing
In late 2007 NMT initiated legal proceedings against Wilmshurst over comments he’d made to heartwire about the MIST controversy, and in late 2007 requested-but was denied-that theheart.org remove its earlier coverage of the MIST controversy.

Lilleyman told heartwire that he believes that the legal dispute between NMT and Wilmshurst may be deflecting attention away from unresolved issues with the trial. “Ignoring the spat between Peter Wilmshurst and NMT, basically what I’m concerned about is that we don’t know what the status of these patients is, and the only way to find out is to review their original scans with an independent, disinterested expert and possibly scan some of them again if the data are nonexistent or noninterpretable,” he said.

Such a step would also help resolve another MIST mystery: to date, it is unclear whether any residual shunting in the MIST trial patients is a result of inadequate PFO closure with the STARFlex device or due to the presence of pulmonary shunts not properly identified at baseline.

The STARFlex PFO occluder is approved in Europe, Canada, and elsewhere for the treatment of cryptogenic stroke; in the US, approval for stroke hangs on the results of the NMT-sponsored CLOSURE I trial, which recently completed enrollment.

While the migraine/PFO theory took a hit with the failure of MIST-at least one other competing closure-device manufacturer abandoned its migraine trial-the theory is not dead altogether. A recent study in JACC:
Cardiovascular Interventions found that 53 migraineurs who underwent PFO closure were significantly more likely to experience migraine disappearance or 50% reductions in migraine attacks at six months than 29 controls who received optimal migraine therapy [2].